Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.
Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients.
复制标题
DOI：
10.1126/scitranslmed.3004916
复制
发表时间：
2013-02-27
影响因子：
17.1
通讯作者：
Greenberg PD
中科院分区：
文献类型：
--
作者：
Chapuis AG;Ragnarsson GB;Nguyen HN;Chaney CN;Pufnock JS;Schmitt TM;Duerkopp N;Roberts IM;Pogosov GL;Ho WY;Ochsenreither S;Wölfl M;Bar M;Radich JP;Yee C;Greenberg PD
复发仍然是高危白血病患者异基因造血细胞移植（HCT）后死亡的主要原因。潜在有益的供体T细胞介导的移植物抗白血病（GVL）效应通常被并发的移植物抗宿主病（GVHD）减轻。提供可选择性靶向肾母细胞瘤抗原1（WT 1）（一种在白血病中过表达的促成恶性表型的转录因子）的T细胞代表了促进抗白血病活性而不诱导GVHD的潜在机会。对11例复发或高危白血病患者进行HCT后给予HLA A*0201限制性WT 1特异性供体来源的CD 8+细胞毒性T细胞（CTL）克隆，无任何靶向毒性证据。最后四名治疗的患者接受暴露于IL-21产生的CTL克隆作为延长体内CTL存活的手段，因为IL-21可以限制体外产生的抗原特异性T细胞的终末分化。转移的细胞在2例患者中表现出抗白血病活性的直接证据：1例晚期进展性疾病患者出现一过性应答，1例微小残留病（MRD）患者诱导长期缓解。此外，3例HCT后复发风险高的治疗患者存活，未发生白血病复发、GVHD或额外的抗白血病治疗。在IL-21存在下产生的CTL在这后三名患者和MRD患者中转移，都保持可检测的长期和维持/获得的体内表型和功能特征，与长寿命记忆CD 8 + T细胞相关。这项研究支持扩大免疫靶向WT 1的努力，并提供了对在患者中建立有效的持续T细胞应答所需条件的见解。
Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T-cell-mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft versus host disease (GVHD). Providing T-cells that can selectively target Wilms’ Tumor Antigen 1 (WT1), a transcription factor over-expressed in leukemias that contributes to the malignant phenotype, represents a potential opportunity to promote anti-leukemic activity without inducing GVHD. HLA A*0201-restricted WT1-specific donor-derived CD8+ cytotoxic T-cell (CTL) clones were administered post-HCT to 11 relapsed or high-risk leukemia patients without any evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to IL-21 as a means to prolong in vivo CTL survival, as IL-21 can limit terminal differentiation of antigen-specific T-cells generated in vitro. Transferred cells exhibited direct evidence of anti-leukemic activity in 2 patients: a transient response in one patient with advanced progressive disease and the induction of a prolonged remission in a patient with minimal residual disease (MRD). Additionally, three treated patients at high risk for relapse post-HCT survive without leukemia relapse, GVHD or additional anti-leukemic treatment. CTL generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long-term and maintained/acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8+ T-cells. This study supports expanding efforts to immunologically target WT1, and provides insights into the requirements necessary to establish potent persistent T-cell responses in patients.
登录
查看更多内容
影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
4.4
作者：
Alves, NL;Arosa, FA;van Lier, RAW
通讯作者：
van Lier, RAW
影响因子：
158.5
作者：
Hunder, Naomi N.;Wallen, Herschel;Yee, Cassian
通讯作者：
Yee, Cassian
影响因子：
20.3
作者：
Gao, LQ;Bellantuono, I;Stauss, HJ
通讯作者：
Stauss, HJ
影响因子：
56.9
作者：
Altman, JD;Moss, PAH;Davis, MM
通讯作者：
Davis, MM